ABSTRACT Recent converging evidence suggests that communication between the immune system and the brain is critical for controlling inflammation. The brain receives information in response to injury induced inflammation in the periphery which in turn initiates a reflex mechanism to suppress immune responses. The resulting neuroendocrine reflex plays an important regulatory role in the immune system. These bidirectional brain-peripheral immune communications operate reflexively, in a closed feedback loop whereby neural circuits can exert significant influence to modulate inflammation. However, the specific mechanisms underlying this brain-immune signaling are largely unknown. Therefore, understanding the distinct molecular and neurophysiological mechanisms that govern these complex pathways is critical, which motivates us to develop new approaches to accurately detect and monitor these changes. We will develop nanosensors for the detection of neurotransmitter release in the peripheral nervous system of axolotls (regenerating salamanders). Our nanosensors are based on a modular platform that can easily be tuned to an appropriate dynamic range, wavelengths for tissue penetration, and size to be compatible with the in vivo environment. The juvenile axolotl is highly transparent and nanosensors injected into the nervous system or organs will be imaged using light sheet fluorescence microscopy. In addition, we have the ability to genetically modify the system to develop a transgenic model that can be stimulated with light to target neuronal excitations, while simultaneously measuring neurotransmitter levels via the fluorescence emitted from the injected nanosensors. Combined, we will image volumetric release of acetylcholine in the peripheral nervous system and spleen of the axolotl, and will translate these results to a mammalian model by the end of the project period.